This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The prevalence of obesity is increasing markedly. Even moderate obesity can contribute to the development of the pathological characteristics of the Metabolic Syndrome. Insulin resistance is the underlying characteristic of Metabolic Syndrome and, along with beta-cell dysfunction, results in Type 2 Diabetes Mellitus (T2DM). Due to the rising incidence of Metabolic Syndrome and T2DM and the limited ability of current treatments to prevent their long-term complications, it is clear that more attention needs to be focused on primary prevention of insulin resistance. In this application we propose to investigate the long-term (1 year) effects of fish oil and [unreadable]-lipoic acid supplementation, alone and in combination, to prevent or attenuate the progression of insulin resistance and dyslipidemia in a nonhuman primate model of diet-induced insulin resistance. The development of insulin resistance in obese rhesus monkeys shares similar features with the progression of metabolic disease in humans. We have previously demonstrated that providing obese rhesus monkeys with a sugar-sweetened beverage daily in combination with ad libitum access to their normal diet for 1 year results in modest weight and body fat gain accompanied by a rapid progression of insulin resistance and dyslipidemia (elevated triglyceride and reduced HDL levels). The use of this model in which rigorous control and compliance with diet and supplement intake can be ensured will allow us to determine the effects of long-term administration of fish oil and [unreadable]-lipoic acid on the progression of thedevelopment and progression of insulin resistance and dyslipidemia. We propose to determine the efficacy of two widely used nutritional supplements known to activate PPARs and/or target lipid dysregulation, inflammation (fish oil), and oxidative stress (alpha-lipoic acid) in this nonhuman primate model. We will pursue the following specific aims: Specific Aim 1: Test the hypothesis that supplementation with fish oil will activate PPARalpha, gamma and delta, increase plasma adiponectin levels, and prevent or attenuate the progression of insulin resistance. Specific Aim 2: Test the hypothesis that supplementation with the potent anti-oxidant, alpha-lipoic acid will reduce oxidative stress and prevent or attenuate the progression of insulin resistance. Specific Aim 3: Test the hypothesis that the effects fish oil in combination with alpha-lipoic acid will be greater than either fish oil or alpha-lipoic acid alone. In addition, we will determine the effects of the supplements on lipid, oxidative stress and inflammatory parameters associated with insulin resistance and cardiovascular risk including substrate oxidation, apolipoprotein-B, lipoprotein particle size, adiponectin, C-reactive protein, homocysteine, interleukin-6, tumor necrosis factor-alpha, monocyte-chemoattractant protein-1, soluble adhesion factors, and PAI-1.